A novel mutation of ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H |
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Authors: | Ohte Satoshi Shin Masashi Sasanuma Hiroki Yoneyama Katsumi Akita Masumi Ikebuchi Kenji Jimi Eijiro Maruki Yuichi Matsuoka Masaru Namba Akira Tomoda Hiroshi Okazaki Yasushi Ohtake Akira Oda Hiromi Owan Ichiro Yoda Tetsuya Furuya Hirokazu Kamizono Jyunji Kitoh Hiroshi Nakashima Yasuharu Susami Takafumi Haga Nobuhiko Komori Tetsuo Katagiri Takenobu |
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Affiliation: | aDepartment of Pharmacology, Chungnam National University College of Pharmacy, Daejeon 305-764, Republic of Korea;bInstitute of Drug Research & Development, Chungnam National University, Daejeon 305-764, Republic of Korea;cDepartment of Medicinal Chemistry, Chungnam National University College of Pharmacy, Daejeon 305-764, Republic of Korea |
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Abstract: | Naphthoquinone derivatives have been reported to possess various pharmacological activities, such as antiplatelet, anticancer, antifungal, and antiviral properties. In this study, we investigated the effects of a newly-synthesized naphthoquinone derivative, 2-decylamino-5,8-dimethoxy-1,4-naphthoquinone (2-decylamino-DMNQ), on VSMC proliferation and examined the molecular basis of the underlying mechanism. In a dose-dependent manner, 2-decylamino-DMNQ inhibited PDGF-stimulated VSMC proliferation with no apparent cytotoxic effect. While 2-decylamino-DMNQ did not affect PDGF-Rβ or Akt, it did inhibit the phosphorylation of Erk1/2 and PLCγ1 induced by PDGF. Moreover, 2-decylamino-DMNQ suppressed DNA synthesis through the arrest of cell cycle progression at the G0/G1 phase, including the suppression of pRb phosphorylation and a decrease in PCNA expression, which was related to the downregulation of cell cycle regulatory factors, such as cyclin D1/E and CDK 2/4. It was demonstrated that both U0126, an Erk1/2 inhibitor, and U73122, a PLCγ inhibitor, increased the proportion of cells in the G0/G1 phase of the cell cycle. Thus, these results suggest that 2-decylamino DMNQ has an inhibitory effect on PDGF-induced VSMC proliferation and the mechanism of this action is through cell cycle arrest at the G0/G1 phase. This may be a useful tool for studying interventions for vascular restenosis in coronary revascularization procedures and stent implantation. |
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Keywords: | Abbreviations: 2-decylamino-DMNQ, 2-decylamino-5,8-dimethoxy-1,4-naphthoquinone VSMCs, vascular smooth muscle cells PDGF, platelet-derived growth factor Erk1/2, extracellular regulated kinases 1/2 PLCγ, phospholipase γ PDGF-Rβ, PDGF receptor β CDK, cyclin-dependent kinase PCNA, proliferative cell nuclear antigen pRb, retinoblastoma protein DMEM, Dulbecco&rsquo s modified Eagle&rsquo s medium FBS, fetal bovine serum PBS, phosphate buffered saline SDS&ndash PAGE, sodium dodecyl sulfate&ndash polyacrylamide gel electrophoresis DMSO, dimethylsulfoxide PI, propidium iodide MAPK, mitogen-activated protein kinase |
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